RT Journal Article
SR Electronic
T1 A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline <em>BRCA1/2</em>-Mutated Ovarian Carcinoma or Other Solid Tumors
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 4095
OP 4106
DO 10.1158/1078-0432.CCR-16-2796
VO 23
IS 15
A1 Kristeleit, Rebecca
A1 Shapiro, Geoffrey I.
A1 Burris, Howard A.
A1 Oza, Amit M.
A1 LoRusso, Patricia
A1 Patel, Manish R.
A1 Domchek, Susan M.
A1 Balmaña, Judith
A1 Drew, Yvette
A1 Chen, Lee-may
A1 Safra, Tamar
A1 Montes, Ana
A1 Giordano, Heidi
A1 Maloney, Lara
A1 Goble, Sandra
A1 Isaacson, Jeff
A1 Xiao, Jim
A1 Borrow, Jen
A1 Rolfe, Lindsey
A1 Shapira-Frommer, Ronnie
YR 2017
UL http://clincancerres.aacrjournals.org/content/23/15/4095.abstract
AB Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I–II study was the first to evaluate single-agent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2–mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2–mutated HGOC. Clin Cancer Res; 23(15); 4095–106. ©2017 AACR.This article is featured in Highlights of This Issue, p. 3975